Venclexta (venetoclax)

Overexpression of anti-apoptotic protein BCL-2 and hypermethylation are hallmarks of acute lymphoblastic leukemia (ALL) and can be pharmacologically addressed by venetoclax (VEN) and hypomethylating agents (HMA) such as azacytidine (AZA) or decitabine (DEC). AZA-induced metabolic suppression as well as overall anti-leukemic activity alone and in combination with VEN was generally weaker compared to DEC. Altogether, we herein demonstrate that combined VEN and HMA application acts synergistically and significantly reduces the leukemic burden in ALL cell lines via impairment of tumor cell metabolism and mitochondrial function.

P1, N=18, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting

P1, N=12, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: May 2026 --> May 2027 | Trial primary completion date: May 2026 --> May 2027

P2, N=120, Recruiting, Chinese PLA General Hospital | Trial primary completion date: Dec 2027 --> Sep 2027

pFAO blockade synergizes with chemotherapy drugs such as venetoclax and cytarabine, enabling exploitation of metabolic vulnerabilities to improve therapeutic outcomes. Integrating solid tumor and leukemia insights, peroxisomes emerge as dynamic lipid-processing organelles coupling FAO, redox buffering, and inter-organelle exchange to cancer persistence. Targeting peroxisome-mediated lipid delivery offers a frontier for overcoming metabolic resilience and therapeutic resistance in leukemia.

Azacitidine was administered after dialysis sessions, while venetoclax dosing was adjusted because of concomitant posaconazole prophylaxis. Approximately one year after diagnosis, relapsed AML was identified on peripheral blood flow cytometry. This case highlights the feasibility of venetoclax-based lower-intensity therapy in selected dialysis-dependent AML patients while underscoring the persistent therapeutic limitations and adverse prognosis associated with relapsed disease in this population.

In this cohort, BRAF-mutant AML patients had poor overall survival with currently available treatments, including venetoclax-based regimens. Drug sensitivity data suggest possible avenues for targeted treatment of BRAF-mutated AML.

Based on treatment regimens, the patients were categorized into chemotherapy group ("3+7"regimen), demethylation therapy (HMA) group (decitabine-based therapy), and UCB group (venetoclax combined with azacitidine plus UCB reinfusion). Cytokine level analysis demonstrated that the direct co-culture group showed higher levels of TNF-α and IFN-γ, as well as lower levels of IL-6 compared to the control group (P<0.001). Immunocytes such as NK cells in UCB may promote immune function reconstruction and hematopoietic recovery in patients, thereby improving their prognosis.

As a result, we found that any possible 2-drug combination of venetoclax, ponatinib, and trametinib was highly synergistic in vitro. Regrettably, none of the synergistic 2-drug combinations appeared sufficiently effective in preventing leukemia outgrowth in our PDX models, which likely requires combinations of >2 drugs. Hence, our results illustrate/signify that straightforward high-throughput combinatorial drug screening in leukemia cell lines is a valid approach to identify synergistic drug combinations that are verifiable in vivo in PDX mouse models without requiring validation in primary patient cells in vitro.

P1/2, N=87, Active, not recruiting, Kerry Rogers | Trial completion date: Apr 2026 --> Apr 2027

P1, N=32, Recruiting, M.D. Anderson Cancer Center | Trial primary completion date: Jun 2026 --> Jun 2028

Univariable and multivariable Cox proportional hazards models were used to evaluate prognostic factors, including age, IPSS-R risk group, hypomethylating agent (HMA) exposure, and venetoclax exposure... The baseline mEASIX was independently associated with overall survival in patients with MDS and appeared most prognostically relevant during early follow-up. These findings suggest that the mEASIX may complement established risk models, although further validation is needed before broader clinical use.